Cisplatin

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Cisplatin
Systematic (IUPAC) name
cis-diamminedichloridoplatinum(II)
Identifiers
CAS number 15663-27-1
ATC code L01XA01
PubChem 84691
DrugBank APRD00359
Chemical data
Formula H6Cl2N2Pt 
Mol. mass 300.05 g/mol
Pharmacokinetic data
Bioavailability complete
Protein binding > 90%
Metabolism  ?
Half life 30-100 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

D(US)
Legal status
Routes Intravenous

Cisplatin, cisplatinum or cis-diamminedichloridoplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. Platinum complexes are formed in cells, which bind and cause cross-linking of DNA -- ultimately triggering apoptosis, or automated cell death.

Contents

[edit] Pharmacology

Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is itself easily displaced, allowing cisplatin to coordinate to a basic site in DNA. Subsequently, the platinum cross-links two bases via displacement of the other chloride ligand.[1] Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible.

Most notable among the DNA changes are the 1,2-intrastrand cross-links with purine bases. These include 1,2-intrastrand d(GpG) adducts which form nearly 90% of the adducts and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts occur but are readily excised by the nucleotide excision repair (NER) . Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. Interaction with cellular proteins, particularly HMG domain proteins, has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action.

Note that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and cannot carry out alkylating reactions. It is correctly classified as alkylating-like.

[edit] Cisplatin Resistance

Cisplatin combination chemotherapy is the cornerstone of treatment of many cancers. Initial platinum responsiveness is high but the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Many mechanisms of cisplatin resistance have been proposed including changes in cellular uptake and efflux of the drug, increased detoxification of the drug, inhibition of apoptosis and increased DNA repair[2]. Oxaliplatin is active in highly cisplatin-resistant cancer cells in the laboratory, however there is little evidence for its activity in the clinical treatment of patients with cisplatin resistant cancer[3]. The drug Paclitaxel may be useful in the treatment of cisplatin resistant cancer, the mechanism for this activity is unknown[4].

[edit] Transplatin

Transplatin, the trans stereoisomer of cisplatin, has formula trans-[PtCl2(NH3)2] and does not exhibit a comparably useful pharmacological effect. Its low activity is generally thought to be due to rapid deactivation of the drug before it can arrive at the DNA.[citation needed] It is toxic, and it is desirable to test batches of cis-platin for the absence of the trans isomer. In a procedure by Woollins et al., which is based on the classic 'Kurnakov test', thiourea reacts with the sample to give derivatives are easily separated and detected by HPLC.[5]

[edit] Side effects

Cisplatin has a number of side-effects that can limit its use:

  • Nephrotoxicity (kidney damage) is a major concern when cisplatin is given. The dose is reduced when the patient's creatinine clearance (a measure of renal function) is reduced. Adequate hydration and diuresis is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen species and in animal models can be ameliorated by free radical scavenging agents. This is a dose-limiting toxicity.
  • Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before and after treatment.
  • Nausea and vomiting. Cisplatin is one of the most emetogenic chemotherapy agents, but this is managed with prophylactic antiemetics (e.g. ondansetron, granisetron, etc.) in combination with corticosteroids. Aprepitant combined with ondansetron and dexamethasone has been shown to be better for highly emetogenic chemotherapy than just ondansetron and dexamethasone.
  • Ototoxicity (hearing loss): unfortunately there is at present no effective treatment to prevent this side effect, which may be severe. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to melanin in the stria vascularis of the inner ear or the generation of reactive oxygen species.
  • Alopecia (hair loss): this is generally not a major problem in patients treated with cisplatin.
  • Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin.

[edit] History

The compound cis-PtCl2(NH3)2 was first described by M. Peyrone in 1845 (known as Peyrone's salt).[6] The structure was deduced by Alfred Werner in 1893.[1] In the 1960s, Barnett Rosenberg and van Camp et al at Michigan State University discovered that electrolysis of a platinum electrode produced cisplatin, which inhibited binary fission in Escherichia coli (E. coli) bacteria. The bacteria grow to 300 times their normal length but cell division fails. Rosenberg then conducted a series of experiments to test the effects various platinum coordination complexes on sarcomas artificially implanted in rats. This study found that cis-diamminedichloridoplatinum(II) was the most effective out of this group, which started the medicinal career of cisplatin.[7]

Approved for clinical use by the United States Food and Drug Administration (FDA) in 1978,[citation needed] it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action, using a variety of spectrocopic methods including X-ray, NMR spectroscopy, and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.

[edit] Synthesis

The synthesis of cisplatin is a classic in inorganic chemistry. Starting from potassium tetrachloroplatinate(II), K2PtCl4, the first NH3 ligand is added to any of the four equivalent positions, but the second NH3 could be added cis or trans to the bound amine ligand. Because Cl− has a larger trans effect than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using PtI42− to ensure high yield and purity of the cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara.[8][9]

Synthesis of cisplatin

[edit] References

  1. ^ a b Stephen Trzaska (20 Jun 05). "Cisplatin". C&EN News 83 (25). 
  2. ^ Stordal, B. and Davey, M. (2007). Understanding cisplatin resistance using cellular models. IUBMB Life. 59(11) 696-699. [1]
  3. ^ Stordal, B., Pavlakis, N. and Davey, R. (2007). Oxaliplatin for the treatment of cisplatin-resistant cancer: A systematic review. Cancer Treatment Reviews. 33(4)347-357 [2]
  4. ^ Stordal, B., Pavlakis, N. and Davey, R. (2007). A systematic review of platinum and taxane resitance from bench to clinic: An inverse relationship. Cancer Treatment Reviews. 33:688-703.[3]
  5. ^ J. D. Woollins, A. Woollins and B. Rosenberg (1983). "The detection of trace amounts of trans-Pt(NH3)2Cl2 in the presence of cis-Pt(NH3)2Cl2. A high performance liquid chromatographic application of kurnakow's test". Polyhedron 2 (3): 175-178. doi:10.1016/S0277-5387(00)83954-6. 
  6. ^ Peyrone M. Ann Chemie Pharm 1845;51:129.
  7. ^ Rosenberg, B.; Van Camp, L.; Krigas, T. (1965). "Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode". Nature 205 (4972): 698-699. doi:10.1038/205698a0. 
  8. ^ Dhara, S. C. Indian Journal of Chemistry 1970, volume 8, pp. 193–134.
  9. ^ Rebecca A. Alderden, Matthew D. Hall, and Trevor W. Hambley (2006). "The Discovery and Development of Cisplatin" (abstract). J. Chem. Ed. 83: 728-724. 

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